rs10870194

Variant names:

• chr9-136432582-A-G
• rs10870194
• NM_019892.6:c.1284T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-136432582-A-G
• chr9-136432582-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001318502.2(INPP5E):​c.1281T>C​(p.Cys427Cys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,540,556 control chromosomes in the GnomAD database, including 151,687 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13778 hom., cov: 32)
  • Exomes 𝑓: 0.44 (137909 hom.)
• Consequence: INPP5E NM_001318502.2 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.92
• Publications: 40 publications found

Genes affected

INPP5E (HGNC:21474): (inositol polyphosphate-5-phosphatase E) The protein encoded by this gene is an inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. InsP3 5-phosphatases hydrolyze Ins(1,4,5)P3, which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimulation. Studies of the mouse counterpart suggest that this protein may hydrolyze phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,5-bisphosphate on the cytoplasmic Golgi membrane and thereby regulate Golgi-vesicular trafficking. Mutations in this gene cause Joubert syndrome; a clinically and genetically heterogenous group of disorders characterized by midbrain-hindbrain malformation and various associated ciliopathies that include retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

INPP5E Gene-Disease associations (from GenCC):

• Joubert syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• MORM syndrome

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, Orphanet
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-136432582-A-G is Benign according to our data. Variant chr9-136432582-A-G is described in ClinVar as Benign. ClinVar VariationId is 129266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318502.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	NM_019892.6	MANE Select	c.1284T>C	p.Gly428Gly	synonymous	Exon 6 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.1281T>C	p.Cys427Cys	splice_region synonymous	Exon 6 of 10	NP_001305431.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1284T>C	p.Gly428Gly	synonymous	Exon 6 of 10	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.1305T>C	p.Gly435Gly	synonymous	Exon 6 of 10	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1281T>C	p.Cys427Cys	splice_region synonymous	Exon 6 of 10	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63907 AN: 151890 Hom.: 13748 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.439

GnomAD2 exomes AF: 0.421 AC: 65329 AN: 155342 AF XY: 0.409

Gnomad AFR exome AF: 0.395

Gnomad AMR exome AF: 0.566

Gnomad ASJ exome AF: 0.439

Gnomad EAS exome AF: 0.194

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.434

GnomAD4 exome AF: 0.441 AC: 611967 AN: 1388546 Hom.: 137909 Cov.: 31 AF XY: 0.437 AC XY: 299396 AN XY: 685382

African (AFR) AF: 0.395 AC: 12410 AN: 31412

American (AMR) AF: 0.566 AC: 20207 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 11123 AN: 25118

East Asian (EAS) AF: 0.226 AC: 8090 AN: 35798

South Asian (SAS) AF: 0.334 AC: 26450 AN: 79082

European-Finnish (FIN) AF: 0.336 AC: 15866 AN: 47206

Middle Eastern (MID) AF: 0.384 AC: 2178 AN: 5674

European-Non Finnish (NFE) AF: 0.458 AC: 490953 AN: 1070890

Other (OTH) AF: 0.428 AC: 24690 AN: 57672

GnomAD4 genome AF: 0.421 AC: 63986 AN: 152010 Hom.: 13778 Cov.: 32 AF XY: 0.414 AC XY: 30795 AN XY: 74296

African (AFR) AF: 0.400 AC: 16578 AN: 41466

American (AMR) AF: 0.528 AC: 8064 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1561 AN: 3464

East Asian (EAS) AF: 0.206 AC: 1064 AN: 5156

South Asian (SAS) AF: 0.327 AC: 1574 AN: 4816

European-Finnish (FIN) AF: 0.326 AC: 3444 AN: 10566

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30295 AN: 67946

Other (OTH) AF: 0.439 AC: 926 AN: 2110

Alfa AF: 0.445 Hom.: 23557

Bravo AF: 0.436

Asia WGS AF: 0.320 AC: 1112 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Joubert syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	Joubert syndrome (1)
-	-	1	MORM syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.13
DANN	Benign	0.36
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10870194; hg19: chr9-139327034; COSMIC: COSV65495989; COSMIC: COSV65495989;